Dring et al.

The EPMA Journal 2012, 3:2

http://www.epmajournal.com/content/3/1/2

REVIEW

Open Access

Exercise in multiple sclerosis an integral

component of disease management
Andrea Dring2*, Caspar F Pfueller1, Friedemann Paul1 and Jan Drr1

Abstract
Multiple sclerosis (MS) is the most common chronic inflammatory disorder of the central nervous system (CNS) in
young adults. The disease causes a wide range of symptoms depending on the localization and characteristics of
the CNS pathology. In addition to drug-based immunomodulatory treatment, both drug-based and non-drug
approaches are established as complementary strategies to alleviate existing symptoms and to prevent secondary
diseases. In particular, physical therapy like exercise and physiotherapy can be customized to the individual
patients needs and has the potential to improve the individual outcome. However, high quality systematic data on
physical therapy in MS are rare. This article summarizes the current knowledge on the influence of physical activity
and exercise on disease-related symptoms and physical restrictions in MS patients. Other treatment strategies such
as drug treatments or cognitive training were deliberately excluded for the purposes of this article.
Keywords: Multiple sclerosis, Physical therapy, Exercise, Prevention of sequelae, Personalized treatment

Background of MS
MS is a chronic inflammatory disease of the CNS, which
causes multifocal demyelination along with astrocytic
gliosis and variable axon loss in the brain and spine. MS
is one of the most common causes of non-traumatic
disability in young adults and approximately 1-2.5 million people around the world are estimated to be
affected, depending on the publication [1,2]. Women are
more likely to develop the disease than men (female:
male ratio approximately 2-3:1). MS usually manifests
between the age of 20 to 40 years, rarely much earlier
during childhood, or in old age. The disease course is
usually relapsing-remitting with progression into a secondary progressive form after a varying period of time
or primary progressive right from the start. The precise
etiology of MS still remains unclear. A combination of
environmental and genetic factors which lead to autoimmune reactions against CNS-structures which in turn
result in CNS tissue damage and neurological impairment is assumed to be the most likely pathomechanism
[2,3].

* Correspondence: andrea.doering@charite.de
2
NeuroCure Clinical Research Center and Clinical and Experimental Research
Center for Multiple Sclerosis, Charit - Universittsmedizin Berlin, Charitplatz
1, 10117 Berlin, Germany
Full list of author information is available at the end of the article

Depending on the localization and characteristics of

the morphological changes in both white and gray
brain matter, different symptoms and signs may occur,
such as visual impairment, dysarthria and dysphagia,
spasticity, paresis, coordination and balance impairment, ataxia, pain, sensory impairment, bladder, bowel
and sexual dysfunction [3-7]. Fatigue, emotional and
cognitive changes are also frequently present in MS
[8-13]. These symptoms, often in combination with a
lack of confidence in ones own capabilities and abilities to manage the symptoms, lead to impaired functional capacity and subsequently reduced physical and
sporting activity as well as reduced quality of life
[14-18]. As in other conditions with reduced mobility,
in MS the lack of physical activity can lead to secondary sequelae such as obesity, osteoporosis, and/or cardiovascular damage which in turn pose a serious threat
to patients as they increase the risk of further complications like thrombosis, pulmonary embolisms, upper
respiratory or urinary tract infections, or prominent
decubital ulcers [15,16,19].
According to the autoimmune etiopathology, immunomodulatory drugs such as interferon-b or glatiramer
acetate are the treatment of choice. If these drugs are
not sufficiently effective, escalation therapy with immunosuppressive substances (mitoxantrone), monoclonal

2011 Dring et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons
Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in
any medium, provided the original work is properly cited.

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antibodies (natalizu-mab) or the recently approved

sphingosinphosphat receptor modulator fingolimod may
be required (Figure 1) [20-22].

Definitions
For the purpose of this article the terms movement,
physical activity, exercise, physical function, physical
therapy, physiotherapy and sport will be used according
to the following definitions (Tables 1 and 2): In terms of
the motor system, the term movement includes an
actively or passively induced change in the position of
the body. Regular exercise and physical activity are decisive factors in a persons quality of life by sustainably
improving health and wellbeing and preventing diseases
at all stages of life. As opposed to sport, in which the
focus is on physical achievement, competition and fun,
physical activity encompasses any type of physical movements, which consume energy, regardless of the underlying motivation. The term health-enhancing physical
activity includes both leisure-time activities (e.g. sport)
and everyday activities (e.g. climbing stairs). The intensity of the activity is categorized according to the metabolic equivalent (MET; 1 MET corresponds to the
oxygen uptake of an adult whilst sitting = 3.5 ml (men)

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and 3.2 ml (women) O2 /kg/min) into light (<3 MET),

moderate (3-6 MET) and vigorous (>6 MET). In contrast to general physical activity, exercise encompasses
the planned performance of systematically repeated
movements to accomplish skills, maintain and
strengthen physical condition, and improve performance. Athletics, more specifically, aims to improve
general flexibility and includes endurance training to
maintain performance over longer periods of time at a
high level and strength training to increase muscle
strength. The terms endurance and aerobic training as
well as resistance and strength training are often used
synonymously. Physical function encompasses a series
of increasingly integrated steps, with the highest level
consisting of the most advanced activities of daily life
(ADL), the fulfillment of societal roles and the pursuit of
recreational activities [16]. The term physiotherapy
includes manual skills, that are appropriately supplemented by remedies like water, heat, light, or electricity
and aims to restore functionality and conscious perception of the human body. Active and/or passive training
programs are part of physiotherapeutic methods. On the
contrary physical therapy is rather used as an
umbrella-term, comprising different kinds of physical

Figure 1 Drug-based and non-drug-based symptomatic treatment approaches for MS complement each other in almost every stage
of disease. Drug-based strategies encompass basic treatments (interferon-b or glatriameracetete) and if these drugs are not sufficiently
effective escalation therapy with immunosuppressive substances (mitoxantrone), monoclonal antibodies (natalizumab) or sphingosinphosphat
receptor modulator fingolimod. Non-drug strategies like physical therapy (physiotherapy, ergotherapy, logopedics, rehabilitaton) and
occupational therapy (sociotherapy and psychotherapy) are used complementarily in all stages of the disease

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Table 1 Definitions of different types of physical movements

Definitions
Movement
Active or passive change in the position of the body
Physical activity Any type of physical movement that consumes the subjects energy
Physical
function

A series of increasing steps, with the highest level consisting of the most advanced activities of daily life, the fulfillment of social
roles and the pursuit of recreational activities

Exercise

Planned performance of systematically repeated movements to accomplish skills, maintain and strengthen physical condition, and
improve performance

Sport

Exercise with a focus on physical achievement, competition, and fun

activity like exercise, (functional) training, physiotherapy,

and rehabilitation.

Symptomatic treatment of MS aiming at a

personalized modification of symptoms and
outcome
Drug-based and non-drug-based symptomatic treatment
approaches for MS complement each other. Drug-based
approaches which are referred to in comprehensive
reviews [21,22] are beyond the scope of this article.
Apart from counseling and nursing care, non-drug strategies encompass physical therapy like physiotherapy,
logopedics, occupational therapy including living and
mobility aids, sociotherapy and psychotherapy (Figure
1). These measures can be applied multimodally, meaning that several approaches are combined in a patients
treatment strategy and should generally complement
drug therapy [4,23,24]. Physical therapies are developed
depending on the individual symptoms and positively
affect several factors at the same time. Importantly,
apart from reducing symptoms, enhancing mobility,
improving quality of life and conferring as much independence as possible, for example by functional training
of ADLs, such as washing, eating, drinking, dressing,
and performing household chores, symptomatic therapies may prevent potentially life-threatening secondary
diseases [15,25]. Physical therapies can be applied in
almost every stage of disease from the first onset of
symptoms to highly impaired patients and palliative
conditions. In contrast to physiotherapy, exercise is not
part of commonly used therapies offered to MS patients;
however it might be a promising and cost-effective tool
to improve various functions in patients with MS.
Exercise in MS patients effects on clinical
parameters (Table 3)
Impairment of MS patients like spasticity or paresis is primarily a consequence of disease progress (morphological
Table 2 Types of human movements, sorted according to
intensity
Type of human movements
Movement Physical activity Physical function Exercise Sport

changes), but it can be aggravated by reduced physical

activity [14,26]. Exercise has been shown to improve various aspects of the physiological profile of MS patients; in
particular, inactivity-related impairment can be alleviated
by exercise [26]. However, recommendations on exercise
for patients with MS have to face a number of limitations:
Although there is a large number of studies on which
recommendations have been based, many of these studies
have limitations, including small sample sizes, lack of an
appropriate control group, unblinded design, and failure
to distinguish between different courses and stages of the
disease. In fact, only occasionally a randomized controlled
and blinded study design is applied. Training regimes are
often not standardized, and the interventions are hardly
sufficiently described. The comparability of studies is
furthermore limited by variable treatment duration
extending over a short period of weeks up to few months,
different treatment frequency and different treatment
intensity. Long term-effects of the respective interventions
are rarely reported [14,27-31]. Furthermore, effects of
exercise have been studied almost exclusively in MS
patients with slight or moderate impairment (score on the
expanded disability status scale (EDSS) less than 7) [14].
To our knowledge only one recently published study
examined highly impaired MS patients with an EDSS of 58 [32].
In summary, despite the often insufficient methodological quality of the studies and the insufficiently
described training regimes [14,29,33] most of these studies including exercise programs of resistance (e.g. progressive resistance exercise, walking mechanics),
endurance (e.g. bicycle ergometry, arm or arm-leg ergometry, aquatic exercise, treadmill walking) as well as
combined training provided evidence for a benefit of
exercise in MS patients [14,15,28,29]. These training
programs are referred to in more detail below. All training programs have been well tolerated by the patients.
Nearly 100% of inpatient participants and 59-96% participants of home-based trials completed without occurrence of adverse events [34-38].
Endurance training

Moderate endurance training resulted in improved muscle strength of both lower and upper extremities and

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Table 3 Overview of selected studies on exercise in multiple sclerosis

Form of
training

Author

Method

(Major) Endpoints

Sample
size

EDSS

Main Results

Comments

Aerobic
training

Newman
[27]

Treadmill walking

Gait parameters,
Fatigue

16

<7

Improvements in some gait

parameters, fatigue
unchanged

Repeated
measures design
and blinded
assessments

Pilutti [32]

Body-weight
supported treadmill
training (BWSTT)

Functional ability,
quality of life,
Fatigue

5,5-8

Patients with
progressive MS of
high disability

Rampello
[42]

Aerobic training
program compared
with neurological
rehabilitation

Walking parameters,
maximal exercise
tolerance, quality of
life, fatigue

19

<6

Improvements in some
functional abilities and some
parameters of quality of life,
Fatigue non-significantly
reduced
Improvements of some
walking parameters after
aerobic training, Fatigue
after aerobic training and
neurological rehabilitation
comparable

Schulz [44]

Aerobic training

Immune-endocrine
parameters,
neurotrophic factors,
quality of life,
coordinative
function

67

<5

Lactate levels lowered,

quality of life increased and
coordinative increased

Van den
Berg [47]

Aerobic treadmill
training

Walking parameters,
fatigue

19

Walk 10 m in
60 s, using aid
if necessary

Improvements of some
walking parameters after
aerobic treadmill training,
fatigue not significantly
reduced

Prospective,
randomized
controlled trial
with blinded
assessments, 16
patients
completed

Mostert
[48]

Aerobic training

26

<6.5

Improvement of health
perception, activity level

Randomized trial

Dodd [28]

Progressive
resistance
strengthening

Aerobic fitness,
fatigue, health
perception, activity
level
Physical,
psychological, social
factors

no information Fatigue reduced significantly Semi-structured

interviews

Dalgas [31] Progressive

resistance training

Muscle strength,
functional capacity

38

3-5.5

Harvey [39] General

physiotherapy
exercises,
strengthening
training

Muscle strength,
functional activities

19

White [30]

Progressive
resistance training

Taylor [40]

Progressive
resistance training

Lower extremity
8
strength, ambulatory
function, fatigue,
disability
9
Maximal muscle
force, muscle
endurance,
functional activity,
psychological
function

Gutierrez
[49]

Resistance training

Kinematic gait
8
parameters, isometric
strength, stepping,
fatigue, disability

2.5-5.5

Increases in some kinematic

gait parameters, fatigue
decreased

Broekmans
[101]

Resistance training

Muscle strength,
functional mobility

2-6.5

Improvements in muscle
strength and some
functional parameters

Resistance
Training

36

Only 11 patients
completed

Muscle strength and

Randomized
functional capacity increased controlled trial
including followup
Ambulant with Muscle strength and
or without the functional activities
use of walking improved
aids
1-5

Lower extremity strength

increased

able to walk at Improvements in muscle

Pre/post single
least 200 m
strength, muscle endurance, group research
without aid or and functional activity
design
rest

Randomized
controlled trial,
long-term
investigation (20
weeks)

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Table 3 Overview of selected studies on exercise in multiple sclerosis (Continued)

Combined
training

Others

Romberg
[34]

Strength, aerobic
training

Walking speed,
95
lower extremity
strength, upper
extremity endurance,
dexterity, static
balance

1-5.5

Cakit [35]

Cycling progressive
resistance training,
balance exercises

Walking parameters, 45
balance, fatigue, fear
of falling, depression,
quality of life

of 6.0, ability Improvements in walking

to stand
parameters, fatigue, fear of
independently falling, depression
in upright
position for >3
s

Randomized (two
exercise training
and one control
group), only 33
patients
completed

Smith [46]

Strengthening,
stretches, fitness
exercises

Function, fatigue,
sensory symptoms

34

0-6

> 40% temporary increased

sensory symptoms (number
or intensity)

Single exercise
session with
follow up, all
measures selfrated

Surakka
[50]

Aerobic and strength Motor fatigue

exercise

95

1-5.5

Motor fatigue reduced in

women (not in men)

Randomized
controlled trial

Motl [17]

Wearing an
accelerometer

292

no information Improvements in disability,

fatigue, depression, pain,
self-efficacy, social support

No specific
training-protocol,
completed selfreport measures

112

0-6.5

Improvements in training
groups with different impact
on parameters, fatigue
reduced

Randomized
(three exercise
training and one
control group),
only 95 patients
completed

42

4.0-5.5

Improvements in mobility,
subjective wellbeing, and
mood

Randomized
controlled
crossover trial

Physical activity,
quality of life,
disability, fatigue,
mood, pain, selfefficacy, social
support
Rasova [43] Neurophysiologically Impairment,
based physiotherapy, disability, handicap,
aerobic training,
quality of life,
combined therapy
fatigue, depression,
respiratory function,
physical fitness
Wiles [51]

Physiotherapy

Mobility, mood

some functional measures like walking speed, fatigue,

and quality of life [14,15,17,28,29,31,34]. Some authors
reported beneficial effects in chair transfer [14,39], gait,
stair climbing, and timed up and go test (standing up
from a chair, walking 3 m, turning around and seat
again) [14,35,40]. But, as described above, varying and
contradictory results were found. For example, some
authors reported marked improvements in aerobic capacity, measured by maximal oxygen uptake (VO2-max),
[14,41,42], whereas others did not observe significant
improvements [14,43,44].
The same applies to fatigue as there is some evidence
for an improvement of fatigue by endurance training
[30,35,45], whereas other studies missed the level of statistical significance [14,28,35] or did not reveal any differences at all [27,46,47].
Contradictory data have been reported on various
items of health related quality of life like vitality [14,48],
social functioning [14,44,48], mood [14,42,44], energy
[14,42], anger [14,41], sexual function [14], bladder and
bowel function [41], and depression [14,41].
One group analyzed the effect of a 6 months outpatient aerobic training program in MS patients with mild

Walking speed improved

6-month exercise
program,
randomized study,
91 patients
completed

to moderate disability (EDSS 1-6) and observed a trend

for larger benefits in more severely disabled than in
less affected patients, but the study is limited by the
small sample size of 19 patients of which only 11
patients completed the study [42]. Therefore, these
results have to be handled with care and further studies are required.
Resistance training

Resistance training is known to enhance muscle strength

in healthy people. In MS patients there is also evidence
for improving muscle strength [35,40]. Furthermore,
beneficial effects on walking speed, stepping endurance,
stair climbing, timed up and go test, self-reported disability, and self-reported fatigue have been described in
MS patients as well as significant improvements in gait
disturbances, measured by Dynamic Gait Index [35,49].
There are different forms of resistance training. One
form, for example, constitutes progressive resistance
exercise (PRE), which according to Taylor et al. comprises the following three principles: 1. perform a small
number of repetitions with relatively high loads until
muscle fatigue is reached, 2. allow sufficient rest between

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exercise for recovery, and 3. increase the load as the ability to generate muscle force development [40].
Cakit et al. examined the effect of PRE by means of
cycling progressive resistance training and lower-limb
strengthening, both combined with balance exercise in a
prospective randomized controlled trial of 45 MS
patients [35]. After 8 weeks, patients in the two training
groups performed better with respect to 10 m walking
test, duration of exercise, and timed up and go test than
patients in the control group who received no intervention. Moreover, the training groups showed evidence for
superior effects on balance, fatigue, depression, and fear
of falling.
Taylor et al. investigated the effect of a 10 week PRE
program on maximal muscle force, muscle endurance,
functional activity, and overall psychological function in
MS patients [40]. The authors reported significant
improvements of arm strength, leg endurance, and fast
walking speed, and a trend towards improvement in the
2-min walk-test and day-to-day life function.
Besides PRE, other training forms like strategies to
promote proper gait mechanics, focusing on weight
bearing, weight shifting, and body positioning, or weightlifting are used [49]. For example, Pilutti et al. examined the effect of resistance exercise in six severely
disabled patients (EDSS 5-8) with progressive MS (five
patients with primary progressive, one patient with secondary progressive disease course) by means of a 12
week course of body-weight supported treadmill training
performed three times weekly for 30 min [32]. The
patients improved in terms of training intensity treadmill walking speed and required body weight support as
well as in physical and mental subscales of a quality of
life questionnaire. Fatigue was not reduced.
Combined endurance and resistance training

Only few authors examined the effect of combined resistance and endurance training in MS. Small improvements both in muscle strength and gait velocity have
been described [14,34,50]. Interestingly, in a comparatively large study on 95 MS patients, Surakka et al.
observed significant training effects after six months of
combined resistance and endurance training only in
women, but not in men, which might be explained by a
25% higher exercise activity in women [50]. Furthermore, Romberg et al. reported significant improvements
in walking speed and upper extremity endurance following six months combined exercise training, whereas
lower extremity strength, VO2-max, static balance, and
manual dexterity did not improve [34].
In 2005, the Cochrane Collaboration published a first
systematical review on the effects of exercise on ADL
and health-related quality of life (HRQoL) and the
effects of physical therapy on various symptoms in MS

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patients [33]. Only controlled, randomized clinical studies on adult MS patients not experiencing an exacerbation at the time were included. Six studies, of which
four have so far only been published as an abstract, analyzed the effects of physical therapy (rehabilitation, physiotherapy, exercise, functional training, independent
home-based training, aquatic exercise) on several disease-related variables compared to a control group that
had not received any physical therapy [36,39,41,51-53].
Three other studies compared the results of two different physical therapy programs. In summary, muscle
strength, movement (changing and maintaining posture,
walking, moving around, timed transfer, walking
cadence), and exercise tolerance tests (modified graded
exercise test, VO2-max, and physiological cost index) all
showed substantial improvement. Mood parameters
(fear, depression) showed only moderate improvement
and EDSS, fatigue, cognitive parameters and ADL
remained unchanged [18,37,48].
Asano et al. assessed the methodological quality of
selected randomized controlled trials (RCT) of exercise
interventions in MS carried out from 1950 to 2007 [29].
They found evidence for positive effects of exercise on
physical and psychosocial functioning and quality of life,
but highlighted a great need for high quality RCTs in
this field.
Exercise in MS patients the impact of body temperature
on disability

In 1890 the German ophthalmologist Wilhelm Uhthoff

(1853-1927) first described visual impairment and paresis occurring after physical activity. Because the
patients body temperature was not recorded, Uhthoff
assumed that the described symptoms were caused by
the physical activity itself and not by the resulting
increased body temperature. Consequently, MS patients
were advised not to engage in exercise
[14-16,19,46,54,55]. In fact, 60-80% of MS patients
experience a reversible (re)occurrence or aggravation of
neurological symptoms in situations with increased body
temperature, for example during vigorous physical activity, fever, or a hot bath [14-16,46,54,55]. As a reference
to the first description, the eponym Uhthoffs phenomenon has been coined. The underlying cause is thought
to be a temperature dysregulation due to dysautonomia
with subsequent temperature-dependent impairment of
the conduction velocity of partially demyelinated axons
[15,16,54,56]. Not until about 1937, numerous systematic investigations revealed the correlation between
increased body temperature and aggravation of
disability.
Another argument for MS patients to avoid exercise
was the assumption that a waste of energy might
aggravate fatigue and reduce ADLs [14] which however

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has never been confirmed. Furthermore, a detrimental

effect of physical activity itself on CNS structures or an
activity-mediated increase of the relapse rate has never
been demonstrated [15,57].
Exercise in MS patients effects on the immune system

It is well known that exercise may influence susceptibility to common infectious diseases like upper respiratory
tract infections in different directions [58]. Whereas vigorous physical activity such as competitive sport can
lead to an increased susceptibility to infections, moderate exercise may contribute to their prevention
[15,19,57-59].
On the immune cell level, physical strain in healthy
subjects has been demonstrated to initially increase the
peripheral lymphocyte count which subsequently falls to
below the initial level after cessation of the physical
activity [19,60,61]. The resulting lymphocyte reduction
was short-lasting with a maximum duration of 3-24 h
[19,58,60] and was shown to be more prominent in Th1
cells than in Th2 cells [61-63]. As Th1 cells primarily
secrete pro-inflammatory cytokines like IFN-g, IL-2, and
TNF-a whereas Th2 rather secrete anti-inflammatory
cytokines such as IL-4, IL-5 and IL-10, exercise can promote a shift from a Th1-mediated pro-inflammatory to
a rather anti-inflammatory Th2-mediated cytokine
milieu [58,60] which is of particular interest because an
imbalance of Th1- and Th2-cells is considered relevant
in MS pathogenesis [62].
Since established immunomodulatory drugs such as
IFN-b or glatiramer acetate exert similar effects on the
immune system, drug treatment and physical activity
may complement each other in terms of modulating the
immune system. The only short lasting effects of exercise on the immune cell level argue for regular and frequent training intervals.
The effect of exercise on cytokine production and
response is less clear and often contradictory
[44,60,62,64], which can in part be explained by different populations studied, different training protocols
and/or different readout parameters and paradigms. For
example, Heesen et al. found similar resting serum concentrations of IFN- g, TNF- a and IL-10 in trained and
untrained MS patients [62], whereas White et al.
reported reduced resting plasma concentrations of IL-4,
IL-10, C-reactive protein (CRP) and IFN- g and a tendency for decreased TNF- a in MS patients upon eight
weeks of PRE. Muscle contractions are thought to stimulate secretion of IL-6 [44,65]. Likewise, contradictory
data have been published on the effect of exercise on
immunoregulatory IL-6 in MS patients [44,64].
Given the neurodegenerative component of MS, the
effect of physical activity, particularly of exercise on
nerve growth factors is of particular importance. In

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rodents, exercise has been shown to stimulate the

release of brain-derived neurotrophic factor (BDNF)
[66], insulin-like growth factor 1 (IGF-1) [67-69] and
vascular endothelial growth factor (VEGF) [70], all of
which support cell proliferation, synaptic plasticity, neuroprotection, and neurogenesis in both physiological
and neuroinflammatory conditions [67,71-74]. Also in
humans exercise seems to modify the secretion of neuroactive proteins [14,67]. In both healthy participants
and MS patients 30 min of moderate ergometry-based
exercise increased the concentrations of BDNF and
nerve growth factor (NGF) [59,75]. Increased hippocampal BDNF concentrations have been measured upon
moderate exercise [67]. Since the hippocampus is crucially involved in learning and memory tasks and modulation of mood, these findings might connect exercise
with slowing of cognitive impairment and stabilization
of affect in MS patients [67]. An increased secretion of
IGF-1 has so far been demonstrated in healthy people
after exercise [76-78]. IGF-1 as an important factor in
development supports cell survival, brain growth and
CNS myelination. During later phases of life IGF-1
might play a role in neuroprotection and synaptic and
cognitive plasticity [67]. Furthermore, exercise increased
the activity of antioxidant enzymes, which might support the role of exercise in neuroprotection [67].
Exercise in MS patients effects on morphology and
imaging findings

Repetitive activation of the motor programs strengthens

the cortical engrams and causes neuroplastic and adaptive processes like improved motor unit activation and
synchronization of firing rates. In contrast periods of
inactivity are associated with opposite effects [35,49,79].
Although data on the effect of physical activity on
brain structural parameters are sparse, some evidence
indicates that physiotherapy and regular fitness training
counteract the structural degeneration of brain tissue in
patients with relapsing-remitting MS and possibly have
a neuroprotective impact. Both grey and white matter
atrophy occurs already in early stages of relapsing-remitting MS [80]. However, patients with a higher level of
aerobic fitness were shown to have a comparatively larger local volume of grey matter in the right post-central
gyrus and midline cortical structures including the frontal medial and the anterior cinguli gyrus and the precuneus somatosensory cortex than unfit patients.
Furthermore higher fitness levels were associated with
greater recruitment of cortical regions whereas lower fitness levels were associated with enhanced anterior cingulated cortex activity [81]. These data should however
be treated with caution as they based on a small sample
of 24 female MS patients with a wide range in disability
(EDSS 0-6) and disease duration (1-18 years).

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MS patients have been shown to have more brain

areas, often bilaterally, activated when performing motor
and cognitive tasks compared to healthy controls, possibly as an expression of neuroplasticity [82-92]. The
degree of ipsilateral activation appears to correlate with
the disease course and severity [85,88,93] and is considered to reflect cortical adaptive reorganization processes
[82,85,86]. For example, in MS patients with primary
progressive disease course movement-associated cortical
activation involved nonmotor areas like the insula and
several multimodal cortical regions in the temporal, parietal, and occipital lobes in addition to the classic
areas of motor planning and execution regions (including the supplementary motor area and the cingulate
motor area) [93]. Morgen et al. reported that thumb
movements of untrained MS patients elicited a more
prominent activation of the contralateral dorsal premotor cortex in fMRI than in healthy controls [85] which
in contrast to healthy controls was not attenuated upon
repetitive thumb movements.
In MS patients the corpus callosum is typically
affected. Besides callosal lesions detected by standard
MRI sequences, diffusion tensor imaging sequences
show ultrastructural damage, reflected by a reduced
fractional anisotropy and increased mean diffusivity
[79,94-98]. Interestingly, in a small study comprising 11
MS patients and healthy controls, Ibrahim et al.
described a significant increase of fractional anisotropy
and mean diffusivity in the corpus callosum after a two
months physiotherapy program of 2 h per week, suggesting that physiotherapy may influence the brain
microstructure in MS [79]. In summary, some data suggest, that effects of exercise in MS patients may be
reflected by morphological changes in the CNS which
may be detectable by advanced imaging techniques.
However, existing data are not yet sufficient to unequivocally prove an impact of exercise on brain structure in
MS.
Personalized exercise in MS patients general and
specific recommendations

At the start of the 1990s the German Federal Health

Monitoring Systems general recommendation of performing a specific health-related training program at
least three times a week was replaced by a more global
perspective, namely the integration of everyday physical
activities. In the situation of MS patients with an often
reduced everyday activity, regular exercise is particularly
important. Apart from improving muscle strength, exercise is intended to improve endurance, muscle tone and
posture stability, the degree of flexibility, endurance and
and should involve both the agonists and antagonists
[15,35]. A physical training program needs to be tailored
to the individual needs and symptoms of a patient.

Page 8 of 13

Factors to be considered include the course and stage of

disease, the degree of disability, age, concomitant diseases and sequelae. Importantly, it has to be ensured
that the patient is not overstrained [14-16].
Compared to healthy people MS patients have a
reduced aerobic capacity [14,26,38], decreased muscle
strength, retarded rate of muscle tension development,
reduced muscle endurance and impaired balance
[14,15,36,99-101]. A relationship between gait speed and
strength parameters has been postulated [102]. Petajan
and White illustrated the level of muscular fitness and
physical activity of MS patients in two pyramids": passive range of motion (ROM) forms the basis of the muscular fitness pyramid and can minimize the risk of
contractures when practiced regularly [16]. The next
step in the pyramid comprises active flexibility and
resistance exercise against or without gravity to maintain
muscle integrity, for example to enable the patient carrying out essential daily functions. A well-rounded program of muscle strengthening exercise represents the
top of the muscular fitness pyramid [16]. ADLs form
the basis of the physical activity pyramid, followed by
built-in inefficiencies, active recreation, and structured
aerobic training programs. Again, design, frequency, and
intensity of training programs have to be tailored to the
individual patient. Weight-supported exercises like ergometry and water exercise are particularly recommended
for patients with motor deficit or balance disturbances
[16].
No specific recommendations for exercise treatment
exist that are universally valid. However, general therapeutic recommendations can be defined. Since exercise
programs have not sufficiently been investigated in
more severely disabled patients, these recommendations
are restricted to MS patients with a maximum EDSS
score of 7 [14,15,34,38]. Any new exercise program
should be initialized by a physiotherapist or exercise
physiologist familiar with the disease [14]. A brief history including impairments in particular within daily
activities should be elicited [16]. Regardless of the type
of exercise, training programs should be uncomplicated
and comprehensible to the patients. If necessary, it
might be advisable to explain training programs in an
illustrated or written form [15]. Patients should be
supervised until they can perform the program adequately and independently [14-16,26]. Exercise programs
should specifically target weaker muscles, and should
preferably encompass multisegmental complex movements [15,35]. The intensity should be increased only
slowly, and not to the point of pain [15]. Special care
should be paid to peripheral nerves; particularly overstretching should be avoided [15]. Training sessions are
recommended to start at a low level, include a light
warm-up, progress according to the patients clinical

Dring et al. The EPMA Journal 2012, 3:2

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state and specific problems, and finally reach light to

moderate intensity [14-16,26]. 10-15 min of daily
stretching to maintain and improve flexibility of muscles
and tendons [15] and recovery time between training
sessions of 24-48 h are recommended [15]. Immobilized
patients or those with severe clinical symptoms should
be individually assisted. Some authors advise that cardiopulmonary function and VO2-max should be assessed
prior to treatment start since MS patients may have
reduced heart rate responses in graded exercise testing,
possibly as an expression of cardiovascular dysautonomia [15,16], although this probably can hardly be implemented in the daily routine. Regarding endurance
training and according to the American College of
Sports Medicine, White and Dressendorfer recommend
using the actual heart rate response to graded exercise
testing for finding the ideal target heart range for training [15]. No symptoms should appear and moderate
intensities ought to be strived, for example by means of
the Borg scale of perceived exertion, which ranges from
6 to 20 (6 means no exertion at all, 20 means maximal exertion). For moderate intensities ranges from 11
to 14 are aspired [15,103]. Depending on the symptoms
and the training program, exercises should be performed
at home, individually, with a training partner, or with a
training group, and may include training equipment
such as elastic bands, additional weights and pulley systems. Due to its social support a training group seems
to be favorable in terms compliance and motivation
[16,28]. To achieve similar effects in home-based training programs, patients should be closely supervised, for
example by visits or telephone calls [16,28]. Most
importantly, the training sessions have to be performed
regularly [14-16,26].
Some special recommendations regarding exercise
training for MS patients have been published. However,
it has to be emphasized that these recommendations
mostly represent personal experiences made by the
authors and are not always supported by high standard
clinical trials. Dalgas et al., for example, recommended
endurance training of approximately 10-40 min duration, with an initial training intensity of 50-70% of VO2max corresponding to 60-80% of maximum heart rate
[14]. According to Dalgas et al., resistance training is
recommended to initially comprise 8-15 repetitions
which can then be increased over several months. The
training should start with 1-3 sets, later 3-4 sets with a
2-4 min break between sets and should be performed
two or three times per week. For heat-sensitive patients
and those who regularly develop Uhthoffs phenomenon
exercise training in the morning or in water at temperatures of 27-28C could be preferable since body temperature is physiologically lower early in the day and
heat generated by physical activity is quickly dissipated

Page 9 of 13

in water [15,16]. Alternatively, cooling before exercise

and/or during physical activity for example by cold
packs may help to prevent Uhthoffs phenomenon
[15,16,55]. Also, resistance instead of endurance training
could be preferable for heat-sensitive patients [14].

Physical therapy approaches to prevent or

alleviate individual target symptoms and signs in
MS
Fatigue

Fatigue, defined as an extreme physical and mental

tiredness inadequate to the preceding demand, is a frequent, often very debilitating symptom in MS, which is
generally difficult to treat [8-10,15,35,104-106]. Approximately 75-90% of all MS patients experience fatigue during disease progression [8,10,16] and some MS patients
end up in a vicious circle: out of a wish to reduce fatigue they decrease physical activity which over time
reduces endurance, muscle strength, and quality of life
and may enhance fatigue, which then thus in turn
further limits physical activity and social life [9,42,49].
Apart from cooling, moderate exercise, particularly aerobic training, seems to have a positive effect on fatigue
[30,35,45]. Because fatigue often increases over the day,
training sessions should be performed in the morning
and must not overexert the patient [104]. Special supports like participation in a training group or attending
psychological support to increase motivation for continuation of training over time could be advantageous in
patients suffering from fatigue [16]. Energy saving strategies are also applied, in which the patient learns to
prior-itize and to perform everyday tasks with a minimum of exertion [4,16,27]. Although a beneficial effect
of moderate exercise on fatigue has been described by
some authors [14,28,35,41], effects are usually insufficient to achieve significant improvements in current
fatigue scales [17,35,45,47,50]. Other studies completely
failed to detect any improvements [33]. One explanation
for contradicting results can be found in the use of different fatigue scales, which focus on physical symptoms,
or in attendant sleep disturbances such as insomnia,
sleep related breathing disorders, restless legs syndrome,
periodic limb movement disorder [104-106]. In conclusion, there is some however not unequivocal evidence
for low to moderate beneficial effects of moderate exercise on fatigue.
Spasticity

With a lifetime prevalence of about 90% spasticity is frequent in MS and has a potential to significantly reduce
quality of life [104]. It leads to limitations in the range
and normal pursuit of movements, results in malpositioning of the joints, and is often accompanied by pain
[24]. Controlled studies on exercise and physiotherapy

Dring et al. The EPMA Journal 2012, 3:2

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for MS-related spasticity are rare; however some evidence for improvements has been reported [104].
Physical therapy measures include active and passive
exercise (e.g. targeted positioning of the patient, passive
exercise using motorized cycles, active treadmill exercise) which can be assisted by a training partner or
training equipment such as elastic bands. Physiotherapeutic techniques according to Bobath or Vojta and proprioceptive neuromuscular facilitation (PNF) are among
the treatments applied. None of these measures has
been proven to be superior [104,107]. It is most important to carry them out regularly and with a sufficient
intensity [4,104]. Light stretching of the affected muscle
groups with duration of approximately 20-60 s should
be performed prior to and after exercise [15].
Pareses

Pareses lead to various physical disabilities, such as difficulty in walking and fine-motor dysfunction. A relationship between gait speed and muscle strength in MS
patients has been shown [14]. As no drug treatment for
pareses exists and antispastic drugs such as baclofen
may also lead to a worsening of existing pareses, physical and occupational therapy techniques are the sole
treatment option. Because of reduced impact of gravity
aquatic training allows patients with even severe pareses
of the lower extremities to perform standing and moving exercises [15,16]. A standing frame can help patients
who are unable to stand, to train torso, limb, and
respiratory muscles and protects against cardiovascular
dysregulation. For immobilized patients, passive range of
motion exercises proximal to the paralyzed region is
recommended [15,16]. Various studies have shown a significant improvement of muscle strength due to exercise
[33,35,40,101]. Furthermore some authors reported beneficial effects in walking speed, stepping endurance, stair
climbing, and timed up and go test [35,40,49]. In summary, evidence suggests that exercise is beneficial in the
treatment of MS-related pareses, however again, only
few, partially inconsistent data are available. Moreover,
effects of exercise have been studied almost exclusively
in MS patients with mild or moderate impairment.

Page 10 of 13

variables as primary outcome parameter. Catteneo et al.,

for example, investigated the effect of balance training
in 44 MS patients in a randomized controlled trial [5].
Two treatment groups received particular balance rehabilitation for three weeks, a third (control) group participated an unspecific training program. In both treatment
groups a reduction of the number of falls and an
improvement in clinical tests of static balance (Berg Balance Scale) and dynamic balance (Dynamic Gait Index)
could be detected. However, in self-assessment scales
patients did not report significant improvements [5].
Another controlled study did not support a beneficial
effect of exercise training on static balance [34].
Cognitive and mood disturbances

Depending on the disease course and stage 45-70% of

MS patients are affected by cognitive impairments like
reduced information processing speed, attentional deficits and episodic memory deficits [12,13,24,104,108] and
60-70% experience mood disturbances [13,109,110].
Some evidence for a positive correlation between aerobic exercise and cognition and brain function in healthy
people has been described [81]. In MS patients, beneficial effects of regular physical activity and exercise on
mood [18,32,35,48] and quality of life [14,15,28,34] have
been repeatedly reported. Valid data on the effect on
cognitive function are hardly available.

Conclusion and outlook

Several lines of evidence suggest that MS patients benefit from regular physical activity and exercise with
respect to clinical, imaging and physiological parameters.
However, the quality of so far realized clinical trials on
exercise training in MS do not always satisfy the
requirements of a high standard study. Moreover,
because of different treatment paradigms and endpoints,
data are often hardly comparable. Thus, many questions
remain still unanswered. In consequence, there is a
great need for standardized high quality and well
described studies that address both short and long term
effects of exercise on clinical and paraclinical parameters
in MS patients with different disease courses and different grades of disability.

Coordination and balance dysfunction

Abnormalities in balance control are frequent symptoms

in MS patients, which restrict patients in their daily living activities and increase risk of falls [5]. Balance skills
like standing and walking, as well as the patients perception of their own balance are important to assess [5].
The sitting position of cycling training is advantageous
for unsteady patients [15,16]. Only a few studies investigated the influence of exercise programs on balance and
coordination in MS and very few have chosen these

Open Access
This article is distributed under the terms of the Creative Commons Attribution Noncommercial License
which permits any noncommercial use, distribution, and
reproduction in any medium, provided the original
author(s) and source are credited.
Acknowledgements
This work was supported by the DFG (Exc 257).

Dring et al. The EPMA Journal 2012, 3:2

http://www.epmajournal.com/content/3/1/2

Author details
1
National Representative of EPMA in Germany. 2NeuroCure Clinical Research
Center and Clinical and Experimental Research Center for Multiple Sclerosis,
Charit - Universittsmedizin Berlin, Charitplatz 1, 10117 Berlin, Germany.
Conflicts of interests
The authors declare that they have no competing interests.
Received: 3 August 2011 Accepted: 2 December 2011
Published: 24 December 2011
References
1. Kantarci O, Wingerchuk D: Epidemiology and natural history of multiple
sclerosis: new insights. Curr Opin Neurol 2006, 19(3):248-54.
2. Compston A, Coles A: Multiple sclerosis. Lancet 2002, 359(9313):1221-31.
3. Compston A, Coles A: Multiple sclerosis. The Lancet 2008,
372(9648):1502-17.
4. Henze T, Rieckmann P, Toyka KV: Symptomatic treatment of multiple
sclerosis. Multiple Sclerosis Therapy Consensus Group (MSTCG) of the
German Multiple Sclerosis Society. Eur Neurol 2006, 56(2):78-105.
5. Cattaneo D, Jonsdottir J, Zocchi M, Regola A: Effects of balance exercises
on people with multiple sclerosis: a pilot study. Clin Rehabil 2007,
21(9):771-81.
6. Darley FL, Brown JR, Goldstein NP: Dysarthria in multiple sclerosis. J
Speech Hear Res 1972, 15(2):229-45.
7. DasGupta R, Fowler CJ: Bladder, bowel and sexual dysfunction in multiple
sclerosis: management strategies. Drugs 2003, 63(2):153-66.
8. Fisk JD, Pontefract A, Ritvo PG, Archibald CJ, Murray TJ: The impact of
fatigue on patients with multiple sclerosis. Can J Neurol Sci 1994,
21(1):9-14.
9. MacAllister WS, Krupp LB: Multiple sclerosis-related fatigue. Phys Med
Rehabil Clin N Am 2005, 16(2):483-502.
10. Krupp LB, Alvarez LA, LaRocca NG, Scheinberg LC: Fatigue in multiple
sclerosis. Arch Neurol 1988, 45(4):435-7.
11. Ziemssen T: Multiple sclerosis beyond EDSS: depression and fatigue. J
Neurol Sci 2009, 277(Suppl 1):S37-41.
12. DeSousa EA, Albert RH, Kalman B: Cognitive impairments in multiple
sclerosis: a review. Am J Alzheimers Dis Other Demen 2002, 17(1):23-9.
13. Chiaravalloti ND, DeLuca J: Cognitive impairment in multiple sclerosis.
Lancet Neurol 2008, 7(12):1139-51.
14. Dalgas U, Stenager E, Ingemann-Hansen T: Multiple sclerosis and physical
exercise: recommendations for the application of resistance-, enduranceand combined training. Mult Scler 2008, 14(1):35-53.
15. White LJ, Dressendorfer RH: Exercise and multiple sclerosis. Sports Med
2004, 34(15):1077-100.
16. Petajan JH, White AT: Recommendations for physical activity in patients
with multiple sclerosis. Sports Med 1999, 27(3):179-91.
17. Motl RW, McAuley E, Snook EM, Gliottoni RC: Physical activity and quality
of life in multiple sclerosis: intermediary roles of disability, fatigue,
mood, pain, self-efficacy and social support. Psychol Health Med 2009,
14(1):111-24.
18. Solari A, Filippini G, Gasco P, Colla L, Salmaggi A, La Mantia L, Farinotti M,
Eoli M, Mendozzi L: Physical rehabilitation has a positive effect on
disability in multiple sclerosis patients. Neurology 1999, 52(1):57-62.
19. Waschbisch A, Tallner A, Pfeifer K, Murer M: Multiple sclerosis and
exercise: effects of physical activity on the immune system. Nervenarzt
2009, 80(6):688-92.
20. Thompson AJ, Toosy AT, Ciccarelli O: Pharmacological management of
symptoms in multiple sclerosis: current approaches and future
directions. Lancet Neurol 2010, 9(12):1182-99.
21. Wiendl H, Toyka KV, Rieckmann P, Gold R, Hartung H-P, Hohlfeld R: Basic
and escalating immunomodulatory treatments in multiple sclerosis:
current therapeutic recommendations. J Neurol 2008, 255(10):1449-63.
22. Mendes A, S MJ: Classical immunomodulatory therapy in multiple
sclerosis: how it acts, how it works. Arq Neuropsiquiatr 2011, 69(3):536-43.
23. Thompson AJ: Neurorehabilitation in multiple sclerosis: foundations, facts
and fiction. Curr Opin Neurol 2005, 18(3):267-71.
24. Kesselring J, Beer S: Symptomatic therapy and neurorehabilitation in
multiple sclerosis. Lancet Neurol 2005, 4(10):643-52.

Page 11 of 13

25. White LJ, McCoy SC, Castellano V, Ferguson MA, Hou W, Dressendorfer RH:
Effect of resistance training on risk of coronary artery disease in women
with multiple sclerosis. Scand J Clin Lab Invest 2006, 66(4):351-5.
26. Gallien P, Nicolas B, Robineau S, Ptrilli S, Houedakor J, Durufle A: Physical
training and multiple sclerosis. Ann Readapt Med Phys 2007, 50(6):373-6,
369-372.
27. Newman MA, Dawes H, van den Berg M, Wade DT, Burridge J, Izadi H: Can
aerobic treadmill training reduce the effort of walking and fatigue in
people with multiple sclerosis: a pilot study. Mult Scler 2007, 13(1):113-9.
28. Dodd KJ, Taylor NF, Denisenko S, Prasad D: A qualitative analysis of a
progressive resistance exercise programme for people with multiple
sclerosis. Disabil Rehabil 2006, 28(18):1127-34.
29. Asano M, Dawes DJ, Arafah A, Moriello C, Mayo NE: What does a
structured review of the effectiveness of exercise interventions for
persons with multiple sclerosis tell us about the challenges of designing
trials? Mult Scler 2009, 15(4):412-21.
30. White LJ, McCoy SC, Castellano V, Gutierrez G, Stevens JE, Walter GA, et al:
Resistance training improves strength and functional capacity in persons
with multiple sclerosis. Mult Scler 2004, 10(6):668-74.
31. Dalgas U, Stenager E, Jakobsen J, Petersen T, Hansen HJ, Knudsen C, et al:
Resistance training improves muscle strength and functional capacity in
multiple sclerosis. Neurology 2009, 73(18):1478-84.
32. Pilutti LA, Lelli DA, Paulseth JE, Crome M, Jiang S, Rathbone MP, et al:
Effects of 12 weeks of supported treadmill training on functional ability
and quality of life in progressive multiple sclerosis: a pilot study. Arch
Phys Med Rehabil 2011, 92(1):31-6.
33. Rietberg MB, Brooks D, Uitdehaag BMJ, Kwakkel G: Exercise therapy for
multiple sclerosis. Cochrane Database Syst Rev 2005, 1:CD003980.
34. Romberg A, Virtanen A, Ruutiainen J, Aunola S, Karppi S-L, Vaara M, et al:
Effects of a 6-month exercise program on patients with multiple
sclerosis: a randomized study. Neurology 2004, 63(11):2034-8.
35. Cakit BD, Nacir B, Gen H, Saraolu M, Karagz A, Erdem HR, et al: Cycling
progressive resistance training for people with multiple sclerosis: a
randomized controlled study. Am J Phys Med Rehabil 2010, 89(6):446-57.
36. DeBolt LS, McCubbin JA: The effects of home-based resistance exercise
on balance, power, and mobility in adults with multiple sclerosis. Arch
Phys Med Rehabil 2004, 85(2):290-7.
37. Lord SE, Wade DT, Halligan PW: A comparison of two physiotherapy
treatment approaches to improve walking in multiple sclerosis: a pilot
randomized controlled study. Clin Rehabil 1998, 12(6):477-86.
38. Kileff J, Ashburn A: A pilot study of the effect of aerobic exercise on
people with moderate disability multiple sclerosis. Clin Rehabil 2005,
19(2):165-9.
39. Harvey L, Smith AD, Jones R: The effect of weighted leg raises on
quadriceps strength, EMG parameters and functional activities in people
with multiple sclerosis. Physiotherapy 1999, 85(3):154-61.
40. Taylor NF, Dodd KJ, Prasad D, Denisenko S: Progressive resistance exercise
for people with multiple sclerosis. Disabil Rehabil 2006, 28(18):1119-26.
41. Petajan JH, Gappmaier E, White AT, Spencer MK, Mino L, Hicks RW: Impact
of aerobic training on fitness and quality of life in multiple sclerosis. Ann
Neurol 1996, 39(4):432-41.
42. Rampello A, Franceschini M, Piepoli M, Antenucci R, Lenti G, Olivieri D, et al:
Effect of aerobic training on walking capacity and maximal exercise
tolerance in patients with multiple sclerosis: a randomized crossover
controlled study. Phys Ther 2007, 87(5):545-55.
43. Rasova K, Havrdova E, Brandejsky P, Zlisov M, Foubikova B, Martinkova P:
Comparison of the influence of different rehabilitation programmes on
clinical, spirometric and spiroergometric parameters in patients with
multiple sclerosis. Mult Scler 2006, 12(2):227-34.
44. Schulz K-H, Gold SM, Witte J, Bartsch K, Lang UE, Hellweg R, et al: Impact of
aerobic training on immune-endocrine parameters, neurotrophic factors,
quality of life and coordinative function in multiple sclerosis. J Neurol Sci
2004, 225(1-2):11-8.
45. Stroud NM, Minahan CL: The impact of regular physical activity on
fatigue, depression and quality of life in persons with multiple sclerosis.
Health Qual Life Outcomes 2009, 7:68.
46. Smith RM, Adeney-Steel M, Fulcher G, Longley WA: Symptom change with
exercise is a temporary phenomenon for people with multiple sclerosis.
Arch Phys Med Rehabil 2006, 87(5):723-7.

Dring et al. The EPMA Journal 2012, 3:2

http://www.epmajournal.com/content/3/1/2

47. van den Berg M, Dawes H, Wade DT, Newman M, Burridge J, Izadi H, et al:
Treadmill training for individuals with multiple sclerosis: a pilot
randomised trial. J Neurol Neurosurg Psychiatr 2006, 77(4):531-3.
48. Mostert S, Kesselring J: Effects of a short-term exercise training program
on aerobic fitness, fatigue, health perception and activity level of
subjects with multiple sclerosis. Mult Scler 2002, 8(2):161-8.
49. Gutierrez GM, Chow JW, Tillman MD, McCoy SC, Castellano V, White LJ:
Resistance training improves gait kinematics in persons with multiple
sclerosis. Arch Phys Med Rehabil 2005, 86(9):1824-9.
50. Surakka J, Romberg A, Ruutiainen J, Aunola S, Virtanen A, Karppi S-L, et al:
Effects of aerobic and strength exercise on motor fatigue in men and
women with multiple sclerosis: a randomized controlled trial. Clin Rehabil
2004, 18(7):737-46.
51. Wiles CM, Newcombe RG, Fuller KJ, Shaw S, Furnival-Doran J, Pickersgill TP,
et al: Controlled randomised crossover trial of the effects of
physiotherapy on mobility in chronic multiple sclerosis. J Neurol
Neurosurg Psychiatr 2001, 70(2):174-9.
52. Carter P, White CM: The effect of a general exercise training on effort of
walking in patients with multiple sclerosis. International World
Confederation for Physical Therapy. Barcelona 2003 [http://www.wcpt.org/
abstracts2003/common/abstracts/1517. html].
53. OConnell R, Murphy RM, Hutchinson M, Cooke G, Cootes S: A controlled
study to assess the effects of aerobic training on patients with multiple
sclerosis. 14th International World Confederation for Physical Therapy.
Barcelona 2003 [http://www. wcpt.org/abstracts2003/common/abstracts/
2105.html].
54. Guthrie TC, Nelson DA: Influence of temperature changes on multiple
sclerosis: critical review of mechanisms and research potential. J Neurol
Sci 1995, 129(1):1-8.
55. White AT, Wilson TE, Davis SL, Petajan JH: Effect of precooling on physical
performance in multiple sclerosis. Mult Scler 2000, 6(3):176-80.
56. Rasminsky M: The effects of temperature on conduction in demyelinated single nerve fibers. Arch Neurol 1973, 28(5):287-92.
57. Schulz K-H, Heesen C: Effects of exercise in chronically ill patients.
Examples from oncology and neurology. Bundesgesundheitsblatt
Gesundheitsforschung Gesundheitsschutz 2005, 48(8):906-13.
58. Gleeson M: Immune function in sport and exercise. J Appl Physiol 2007,
103(2):693-9.
59. Gold SM, Schulz K-H, Hartmann S, Mladek M, Lang UE, Hellweg R, et al:
Basal serum levels and reactivity of nerve growth factor and brainderived neurotrophic factor to standardized acute exercise in multiple
sclerosis and controls. J Neuroimmunol 2003, 138(1-2):99-105.
60. White LJ, Castellano V: Exercise and brain health-implications for multiple
sclerosis: Part II-immune factors and stress hormones. Sports Med 2008,
38(3):179-86.
61. Steensberg A, Toft AD, Bruunsgaard H, Sandmand M, Halkjaer-Kristensen J,
Pedersen BK: Strenuous exercise decreases the percentage of type 1 T
cells in the circulation. J Appl Physiol 2001, 91(4):1708-12.
62. Heesen C, Gold SM, Hartmann S, Mladek M, Reer R, Braumann K-M, et al:
Endocrine and cytokine responses to standardized physical stress in
multiple sclerosis. Brain Behav Immun 2003, 17(6):473-81.
63. Lancaster GI, Halson SL, Khan Q, Drysdale P, Wallace F, Jeukendrup AE, et al:
Effects of acute exhaustive exercise and chronic exercise training on
type 1 and type 2 T lymphocytes. Exerc Immunol Rev 2004, 10:91-106.
64. Castellano V, Patel DI, White LJ: Cytokine responses to acute and chronic
exercise in multiple sclerosis. J Appl Physiol 2008, 104(6):1697-702.
65. Ozenci V, Kouwenhoven M, Link H: Cytokines in multiple sclerosis:
methodological aspects and pathogenic implications. Mult Scler 2002,
8(5):396-404.
66. Vaynman S, Ying Z, Gomez-Pinilla F: Hippocampal BDNF mediates the
efficacy of exercise on synaptic plasticity and cognition. Eur J Neurosci
2004, 20(10):2580-90.
67. White LJ, Castellano V: Exercise and brain health-implications for multiple
sclerosis: Part 1-neuronal growth factors. Sports Med 2008, 38(2):91-100.
68. Trejo JL, Carro E, Torres-Aleman I: Circulating insulin-like growth factor I
mediates exercise-induced increases in the number of new neurons in
the adult hippocampus. J Neurosci 2001, 21(5):1628-34.
69. Lopez-Lopez C, LeRoith D, Torres-Aleman I: Insulin-like growth factor I is
required for vessel remodeling in the adult brain. Proc Natl Acad Sci USA
2004, 101(26):9833-8.

Page 12 of 13

70. Fabel K, Fabel K, Tam B, Kaufer D, Baiker A, Simmons N, et al: VEGF is

necessary for exercise-induced adult hippocampal neurogenesis. Eur J
Neurosci 2003, 18(10):2803-12.
71. Black JE, Isaacs KR, Anderson BJ, Alcantara AA, Greenough WT: Learning
causes synaptogenesis, whereas motor activity causes angiogenesis, in
cerebellar cortex of adult rats. Proc Natl Acad Sci USA 1990,
87(14):5568-72.
72. Kleim JA, Cooper NR, VandenBerg PM: Exercise induces angiogenesis but
does not alter movement representations within rat motor cortex. Brain
Res 2002, 934(1):1-6.
73. Swain RA, Harris AB, Wiener EC, Dutka MV, Morris HD, Theien BE, et al:
Prolonged exercise induces angiogenesis and increases cerebral blood
volume in primary motor cortex of the rat. Neuroscience 2003,
117(4):1037-46.
74. Christie BR, Eadie BD, Kannangara TS, Robillard JM, Shin J, Titterness AK:
Exercising our brains: how physical activity impacts synaptic plasticity in
the dentate gyrus. Neuromolecular Med 2008, 10(2):47-58.
75. Griffin EW, Mulally S, Foley C, Warmington SA, OMara SM, Kelly AM:
Aerobic exercise improves hippocampal function and increases BDNF in
the serum of young adult males. Physiol Behav 2011, 104:934-41.
76. Rojas Vega S, Knicker A, Hollmann W, Bloch W, Strder HK: Effect of
resistance exercise on serum levels of growth factors in humans. Horm
Metab Res 2010, 42(13):982-6.
77. Frystyk J: Exercise and the growth hormone-insulin-like growth factor
axis. Med Sci Sports Exerc 2010, 42(1):58-66.
78. Nishida Y, Matsubara T, Tobina T, Shindo M, Tokuyama K, Tanaka K, et al:
Effect of low-intensity aerobic exercise on insulin-like growth factor-I
and insulin-like growth factor-binding proteins in healthy men. Int J
Endocrinol 2010, doi:10.1155/2010/452820.
79. Ibrahim I, Tintera J, Skoch A, Jir F, Hlustik P, Martinkova P, et al: Fractional
anisotropy and mean diffusivity in the corpus callosum of patients with
multiple sclerosis: the effect of physiotherapy. Neuroradiology 2011,
53:917-26.
80. Chard DT, Griffin CM, Parker GJM, Kapoor R, Thompson AJ, Miller DH: Brain
atrophy in clinically early relapsing-remitting multiple sclerosis. Brain
2002, 125(Pt 2):327-37.
81. Prakash RS, Snook EM, Erickson KI, Colcombe SJ, Voss MW, Motl RW, et al:
Cardiorespiratory fitness: A predictor of cortical plasticity in multiple
sclerosis. Neuroimage 2007, 34(3):1238-44.
82. Cifelli A, Matthews PM: Cerebral plasticity in multiple sclerosis: insights
from fMRI. Mult Scler 2002, 8(3):193-9.
83. Rocca MA, Falini A, Colombo B, Scotti G, Comi G, Filippi M: Adaptive
functional changes in the cerebral cortex of patients with nondisabling
multiple sclerosis correlate with the extent of brain structural damage.
Ann Neurol 2002, 51(3):330-9.
84. Colcombe SJ, Kramer AF, Erickson KI, Scalf P, McAuley E, Cohen NJ, et al:
Cardiovascular fitness, cortical plasticity, and aging. Proc Natl Acad Sci
USA 2004, 101(9):3316-21.
85. Morgen K, Kadom N, Sawaki L, Tessitore A, Ohayon J, McFarland H, et al:
Training-dependent plasticity in patients with multiple sclerosis. Brain
2004, 127(Pt 11):2506-17.
86. Lee M, Reddy H, Johansen-Berg H, Pendlebury S, Jenkinson M, Smith S,
et al: The motor cortex shows adaptive functional changes to brain
injury from multiple sclerosis. Ann Neurol 2000, 47(5):606-13.
87. Reddy H, Narayanan S, Arnoutelis R, Jenkinson M, Antel J, Matthews PM,
et al: Evidence for adaptive functional changes in the cerebral cortex
with axonal injury from multiple sclerosis. Brain 2000, 123(Pt 11):2314-20.
88. Pantano P, Iannetti GD, Caramia F, Mainero C, Di Legge S, Bozzao L, et al:
Cortical motor reorganization after a single clinical attack of multiple
sclerosis. Brain 2002, 125(Pt 7):1607-15.
89. Staffen W, Mair A, Zauner H, Unterrainer J, Niederhofer H, Kutzelnigg A,
et al: Cognitive function and fMRI in patients with multiple sclerosis:
evidence for compensatory cortical activation during an attention task.
Brain 2002, 125(Pt 6):1275-82.
90. Penner I-K, Rausch M, Kappos L, Opwis K, Rad EW: Analysis of impairment
related functional architecture in MS patients during performance of
different attention tasks. J Neurol 2003, 250(4):461-72.
91. Filippi M, Rocca MA, Mezzapesa DM, Falini A, Colombo B, Scotti G, et al: A
functional MRI study of cortical activations associated with object
manipulation in patients with MS. Neuro-image 2004, 21(3):1147-54.

Dring et al. The EPMA Journal 2012, 3:2

http://www.epmajournal.com/content/3/1/2

92. Chiaravalloti N, Hillary F, Ricker J, Christodoulou C, Kalnin A, Liu W-C, et al:

Cerebral activation patterns during working memory performance in
multiple sclerosis using FMRI. J Clin Exp Neuropsychol 2005, 27(1):33-54.
93. Rocca MA, Matthews PM, Caputo D, Ghezzi A, Falini A, Scotti G, et al:
Evidence for widespread movement-associated functional MRI changes
in patients with PPMS. Neurology 2002, 58(6):866-72.
94. Roosendaal SD, Geurts JJG, Vrenken H, Hulst HE, Cover KS, Castelijns JA,
et al: Regional DTI differences in multiple sclerosis patients. Neuroimage
2009, 44(4):1397-403.
95. Cassol E, Ranjeva J-P, Ibarrola D, Mkies C, Manelfe C, Clanet M: Diffusion
tensor imaging in multiple sclerosis: a tool for monitoring changes in
normal-appearing white matter. Mult Scler 2004, 10(2):188-96.
96. Coombs BD, Best A, Brown MS, Miller DE, Corboy J, Baier M, et al: Multiple
sclerosis pathology in the normal and abnormal appearing white matter
of the corpus callosum by diffusion tensor imaging. Mult Scler 2004,
10(4):392-7.
97. Guo AC, MacFall JR, Provenzale JM: Multiple sclerosis: diffusion tensor MR
imaging for evaluation of normal-appearing white matter. Radiology
2002, 222(3):729-36.
98. Lenzi D, Conte A, Mainero C, Frasca V, Fubelli F, Totaro P, et al: Effect of
corpus callosum damage on ipsilateral motor activation in patients with
multiple sclerosis: a functional and anatomical study. Hum Brain Mapp
2007, 28(7):636-44.
99. Schwid SR, Thornton CA, Pandya S, Manzur KL, Sanjak M, Petrie MD, et al:
Quantitative assessment of motor fatigue and strength in MS. Neurology
1999, 53(4):743-50.
100. Chen WY, Pierson FM, Burnett CN: Force-time measurements of knee
muscle functions of subjects with multiple sclerosis. Phys Ther 1987,
67(6):934-40.
101. Broekmans T, Roelants M, Feys P, Alders G, Gijbels D, Hanssen I: Effects of
long-term resistance training and simultaneous electro-stimulation on
muscle strength and functional mobility in multiple sclerosis. Mult Scler
2011, 17(4):468-77.
102. Mevellec E, Lamotte D, Cantalloube S, Amarenco G, Thoumie P:
Relationship between gait speed and strength parameters in multiple
sclerosis. Ann Readapt Med Phys 2003, 46(2):85-90.
103. Meyer T, Broocks A: Therapeutic impact of exercise on psychiatric
diseases: guidelines for exercise testing and prescription. Sports Med
2000, 30(4):269-79.
104. de Sa JCC, Airas L, Bartholome E, Grigoriadis N, Mattle H, Oreja-Guevara C,
et al: Symptomatic therapy in multiple sclerosis: a review for a
multimodal approach in clinical practice. Ther Adv Neurol Disord 2011,
4(3):139-68.
105. Veauthier C, Radbruch H, Gaede G, Pfueller CF, Drr J, Bellmann-Strobl J,
et al: Fatigue in multiple sclerosis is closely related to sleep disorders: a
polysomnographic cross-sectional study. Mult Scler 2011, 17(5):613-22.
106. Veauthier C, Paul F: Fatigue in multiple sclerosis: which patient should be
referred to a sleep specialist? Mult Scler 2011, doi:10.1177/
1352458511411229.
107. Paci M: Physiotherapy based on the Bobath concept for adults with
post-stroke hemiplegia: a review of effectiveness studies. J Rehabil Med
2003, 35(1):2-7.
108. Weinges-Evers N, Brandt AU, Bock M, Pfueller CF, Drr J, Bellmann-Strobl J,
et al: Correlation of self-assessed fatigue and alertness in multiple
sclerosis. Mult Scler 2010, 16(9):1134-40.
109. Lincoln NB, Yuill F, Holmes J, Drummond AE, Constantinescu CS,
Armstrong S, et al: Evaluation of an adjustment group for people with
multiple sclerosis and low mood: a randomized controlled trial. Mult
Scler 2011, 17:1250-7.
110. Feinstein A: Mood disorders in multiple sclerosis and the effects on
cognition. J Neurol Sci 2006, 245(1-2):63-6.
doi:10.1007/s13167-011-0136-4
Cite this article as: Dring et al.: Exercise in multiple sclerosis an
integral component of disease management. The EPMA Journal 2012 3:2.

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